Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu 4 )

Sean R. Bollinger, Darren W. Engers, Joseph D. Panarese, Mary West, Julie L. Engers, Matthew T. Loch, Alice L. Rodriguez, Anna L. Blobaum, Carrie K. Jones, Analisa Thompson Gray, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R. Hopkins

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu 4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu 4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC 50 = 50.1 nM, 50.5% GluMax) and selective mGlu 4 PAM with an excellent rat DMPK profile (in vivo rat CL p = 3.1 mL/min/kg, t 1/2 = 445 min, CYP1A2 IC 50 > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)342-358
Number of pages17
JournalJournal of Medicinal Chemistry
Volume62
Issue number1
DOIs
StatePublished - Oct 1 2019

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Cytochrome P-450 CYP1A2
Structure-Activity Relationship
Catalepsy
Haloperidol
Parkinson Disease
Rodentia
metabotropic glutamate receptor 4

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu 4 ) . / Bollinger, Sean R.; Engers, Darren W.; Panarese, Joseph D.; West, Mary; Engers, Julie L.; Loch, Matthew T.; Rodriguez, Alice L.; Blobaum, Anna L.; Jones, Carrie K.; Thompson Gray, Analisa; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.

In: Journal of Medicinal Chemistry, Vol. 62, No. 1, 01.10.2019, p. 342-358.

Research output: Contribution to journalArticle

Bollinger, Sean R. ; Engers, Darren W. ; Panarese, Joseph D. ; West, Mary ; Engers, Julie L. ; Loch, Matthew T. ; Rodriguez, Alice L. ; Blobaum, Anna L. ; Jones, Carrie K. ; Thompson Gray, Analisa ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Niswender, Colleen M. ; Hopkins, Corey R. / Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu 4 ) In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 1. pp. 342-358.
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